rs397517149

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PS2PP2PP3PS3

This summary comes from the ClinGen Evidence Repository: The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234977/MONDO:0018997/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 2.24

Variant links:

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.1642A>C	p.Ser548Arg	missense_variant	Exon 10 of 23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 link	c.1642A>C	p.Ser548Arg	missense_variant	Exon 10 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461112

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 4

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1642A>C p.Ser548Arg variant in the SOS1 gene which is located in a mutational hot spot has been reported previously in a heterozygous state in individuals affected with RASopathies and Noonan syndrome. Published functional studies showed that p.S548R exhibited a significant increase in exchange rate of RAS Santoro et al., 2018; Smith et al., 2013. The amino acid Ser at position 548 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic Multiple submitters. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ser548Arg in SOS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jan 07, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals with Noonan syndrome (Lepri et al., 2011; Hakami et al., 2016; Pierpont et al., 2009; Simsek-Kiper et al., 2013); Published functional studies showed that p.(S548R) exhibited a significant increase in exchange rate of RAS (Smith et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar Variant ID# 40678; SCV000616385.3 ); This variant is associated with the following publications: (PMID: 17143282, 17143285, 24803665, 26918529, 19077116, 22420426, 28456002, 31370276, 31560489, 29493581, 20133692, 23885229, 22465605, 19020799, 23487764, 21387466) -

Mar 05, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 1

Pathogenic:2

Molecular Genetics, Centre for Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Centre for Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported by the ClinGen RASopathy Expert Panel as mutational hotspot of SOS1. In silico predictions suggest that this change may impact the protein. This variant is reported as a pathogenic variant in ClinVar (Variation ID: 40678).In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. -

Noonan syndrome

Pathogenic:2

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong. -

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser548Arg variant in SOS1 has been reported in >10 individuals with clinic al features of Noonan syndrome and was de novo in at least 2 of these individual s (Tartaglia 2007, Roberts 2007, Lepri 2011, LMM unpublished data). It was absen t from large population studies. In vitro functional studies provide some eviden ce that the p.Ser548Arg variant may impact protein function (Smith et al., 2013) . In summary, this variant meets our criteria to be classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Oct 24, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 548 of the SOS1 protein (p.Ser548Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 17143285, 19020799, 19077116, 20186801, 21387466, 22420426, 22465605). ClinVar contains an entry for this variant (Variation ID: 40678). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692, 23487764). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.75

Sift

Benign

0.057

T;T;T

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.75

Gain of MoRF binding (P = 0.0141);Gain of MoRF binding (P = 0.0141);Gain of MoRF binding (P = 0.0141);

MVP

0.97

MPC

1.6

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over